Non insulin-dependent diabetes mellitus (NIDDM) is a disease in which normal fuel homeostasis is perturbed by the combined lesions of insulin resistance, poorly controlled hepatic glucose production, and pancreatic islet beta-cell dysfunction. For the past five years, our laboratory has been investigating the use of high efficiency gene transfer methods to identify genes that can reverse the metabolic abnormalities found in liver and pancreatic islet beta-cells in diabetes and obesity. Based on our findings over this time period, we will focus on the following three specific aims. Specific Aim 1: To deliver genes encoding members of the glycogen targeting subunit gene family to liver of animal models of NIDDM (ZDF rats, diet-induced obesity rats (DIO)), and to determine whether such maneuvers result in normalization of blood glucose without the complication of exacerbated hyperlipidemia. This will include comparison of the muscle-specific (GM), liver-specific (GL) and "ubiquitous" (PTG) members of the gene family, which exhibit distinct regulatory properties; Specific Aim 2: To investigate the role of glycogen and glycogen targeting subunits in beta-cell dysfunction. These studies are build on our recent finding of large increases in expression of two glycogen targeting subunits in islets of ZDF rats, accompanying profound glycogen over-accumulation. We will over-express glycogen over- accumulation and impair beta-cell performance. We will also over- express glycogen phosphorylase in islets of ZDF rats, and will determine whether this maneuver results in restoration of insulin secretion in response to glucose and its potentiators; Specific Aim 3: To investigate the role of lipid over-storage in development of beta-cell dysfunction. We will determine whether reduction in triglyceride (TG) levels restores secretory function in islets from ZDF and DIO rats. This will be accomplished by expression of genes that activate lipolysis and/or fatty acid oxidation such as hormone sensitive lipase, malonyl CoA decarboxylase, malonyl CoA decarboxylase, and uncoupling proteins. If successful, these experiments could be directly applicable to the development of new therapies for obesity and NIDDM.